The invention relates to a drug-containing o/w type fat emulsion for oral administration.
In order that the drug administered orally may be absorbed from the gastrointestinal tract, it is generally necessary that the drug be dissolved within the digestive tract in advance. Therefore, when the drug is a so-called lipophilic drug which is sparingly soluble in the digestive tract, improvements in its gastrointestinal absorption are generally sought by increasing its intra-gastrointestinal solubility through a variety of techniques such as salt formation, modification of crystal form, comminution, and use of a surfactant.
It may also be regarded as one of such pharmaceutical techniques to entrap a drug in fat emulsion particles and administer the resulting fat emulsion. Entrapping a drug in fat emulsion particles stabilizes the drug and improves its dispersibility in the digestive tract, with the result that increases in absorption area and solubility can be expected.
A fat emulsion comprising fat emulsion particles having an average particle diameter of not greater than 200 nm is also known (e.g. Tokkyo Kokai Koho H2-203) and it is generally considered that this emulsion can be administered orally and parenterally. There also is some literature describing pharmaceutical products for oral administration which are based on fat emulsions of relatively large particle size (e.g. Tokkyo Kokai Koho S61-56122).
However, it is suspected that when the conventional fat emulsion is administered orally, the emulsion particles of the fat emulsion are, destroyed by the enzymes in the digestive tract so that the components of the fat emulsion particle are absorbed independently of one another into the absorbing cells, with the result that even when a drug is administered orally in the form of a fat emulsion, the pharmacokinetics of the drug contained in the fat emulsion particles do not agree with the pharmacokinetics of the fat emulsion particles as such which apply to direct administration into the blood vessel. Therefore, when the conventional fat emulsion is administered orally, it seems difficult to achieve the expected effect in terms of absorption, avoidance of metabolism, and transfer to the target tissue.
In addition, the fat emulsion particles of the conventional fat emulsion are destroyed in the digestive tract, it seems difficult to find a correlation between the particle diameter of the particles constituting the fat emulsion and the bioavailability or blood concentration of the drug after oral administration or avoid recognition by the p-glycoprotein (discharging pump) in the absorbing cells of the digestive tract.
The invention has for its object to provide a medical o/w type fat emulsion for oral medication which insures a high bioavailability or blood concentration of a drug.
After intensive research the inventors of the invention found a medical o/w type fat emulsion capable of accomplishing the above object and have developed the invention.
The invention relates to an o/w fat emulsion in which fat emulsion particles composed essentially of an oil component, an emulsifier, and a drug are dispersed in water, characterized in that the average particle diameter of the fat emulsion particles is within the range of 5-50 nm, or a freeze-dried version of said emulsion. The invention further relates to an o/w fat emulsion for oral administration in which fat emulsion particles composed essentially of an oil component, a phospholipid, bile acid or a salt of bile acid, and a drug are dispersed in water, characterized in the average particle diameter of said fat emulsion particles lies within the range of 5-50 nm. By the use of a phospholipid and bile acid or a salt of bile acid in combination, the absorption of the drug from the gastrointestinal tract may be further enhanced.
The invention is now described in detail.
The oil component for use in the invention is not particularly restricted provided that it is an oil component which can be used in pharmaceutical products, thus including vegetable oil, animal oil, neutral lipid (mono-substituted, di-substituted or tri-substituted glyceride), synthetic oil or fat, and sterol derivatives. More particularly, the vegetable oil includes but is not limited to soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil and safflower oil; the animal oil includes but is not limited to fish oil; the neutal lipid includes but is not limited to triolein, trilinolein, tripalmitin, tristearin, trimyristin and triarachidonin; the synthetic lipid includes but is not limited to azone; and the sterol derivatives include but are not limited to cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate and cholesteryl arachidate. Optionally, more than one of those substances may be employed in combination. The preferred oil component includes triglycerides and vegetable oils composed predominantly thereof. Soybean oil is preferred for practical purposes and, in particular, soybean oil purified to a high purity grade is preferred.
The oil component content of the fat emulsion for oral administration according to the invention (hereinafter referred to as xe2x80x9cthe emulsion of the inventionxe2x80x9d) should vary according to species of the oil component used and other components but may judiciously be somewhere within the range of 0.1-30 w/v %, preferably 1-20 w/v %. The same range applies as well to the invention wherein bile acid or a salt of bile acid is one of the essential components of the fat emulsion particle.
The emulsifier for use in the invention is not particularly restricted provided that it can be used in pharmaceutical products, thus including phospholipids and nonionic surfactants. More particularly, the phospholipid includes but is not limited to phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, sphingomyelin and lecithin. Hydrogenated phospholipids can also be used. The nonionic surfactant includes but is not limited to polyalkylene glycols (e.g. a polyethylene glycol with an average molecular weight of 1000-10000, preferably 4000-6000), polyoxyalkylene copolymers (e.g. a polyoxyethylene-polyoxypropylene copolymer with an average molecular weight of 1000-20000, preferably 6000-10000), hydrogenated castor oil-polyoxyalkylene derivatives (e.g. hydrogenated castor oil-polyoxyethylene(20)-ether, (40)-ether, and (100)-ether), and castor oil-polyoxyalkylene derivatives (e.g. castor oil-polyoxyethylene (20)-ether, (40)-ether, and (100)-ether). Those may be used in a combination of two or more different species. As the preferred emulsifier, egg yolk phosphatidylcholine, egg yolk lecithin and soybean lecithin can be mentioned. For practical purposes, egg yolk lecithin and soybean lecithin are preferred. As the phospholipid for use in the invention wherein bile acid or a salt of bile acid is used as an essential component, too, egg yolk phosphatidylcholine, egg yolk lecithin and soybean lecithin are preferred.
The emulsifier content of the emulsion of the invention varies with different species of the emulsifier and other components but may judiciously be somewhere within the range of 0.05-40 w/v %, preferably 0.1-20 w/v %. The same range applies as well to the phospholipid for use in the invention wherein bile acid or a salt of bile acid is used as one of the essential components.
The bile acid or the salt of bile acid, which can be used in the invention, includes but is not limited to taurocholic acid, sodium taurocholate, glycocholic acid, sodium glycocholate, sodium taurodeoxycholate, deoxycholic acid and sodium deoxycholate. Those compounds can be used in a combination of two or more species. As the preferred bile acid or salt of bile acid, taurocholic acid and sodium taurocholate can be mentioned. Particularly when the phospholipid is lecithin, the concominant use of sodium taurocholate as said bile acid or salt of bile acid is preferred.
The bile acid or bile acid salt content of the emulsion of the invention should vary with different species of bile acid or equivalent used and other components but may judiciously be somewhere within the range of 0.05-40 w/v %, preferably 0.1-20 w/v %.
The weight ratio of the oil component to the emulsifier (oil/emulsifier) can be judiciously selected from the range of 0.1-20, preferably 0.4-6.0, more preferably 0.8-1.2 (1 in particular). The weight ratio of the oil component to the phospholipid and the bile acid or salt of bile acid (oil/phospholipid plus bile acid or salt of bile acid) may be judiciously selected from the range of 0.1-20, preferably 0.4-6.0, more preferably 0.8-1.2 (1 in particular).
The drug for use in the invention is, not particularly restricted but is preferably a drug which is generally referred to as a lipophilic drug. Moreover, since the emulsion of the invention is not destroyed by gastrointestinal enzymes but is absorbed in a substantially intact vesicular form, it is particularly useful for the delivery of drugs recognized by p-glycoprotein. Among such drugs are cyclosporin, adriamycin, vincristine and bleomycin. The P-glycoprotein exists on the cell membrane of cerebral vascular endothelial cells and gastrointestinal tract cells and is known to be a protein having a pumping action which recognizes any foreign matter entering the cell and pumps it out from the cell [e.g. Yuzuru Tatsuta et al., Protein, Nucleic Acid and Enzyme, 38, 1501-1509 (1993)].
The drug content of the emulsion of the invention should vary with different kinds of drugs and other components but may judiciously be selected from the range of 0.05-20 w/v %.
Furthermore, in the practice of the invention, an auxiliary emulsifier/emulsion stabilizer can be added. As examples of such auxiliary emulsifier/emulsion stabilizer, there can be mentioned straight-chain or branched-chain saturated or unsaturated fatty acids of 6-22 carbon atoms, specifically stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid and their salts [e.g. alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt etc.), etc.], aliphatic primary amines or aliphatic secondary amines containing 2-22 carbon atoms, specifically ethanolamine, propylamine, octylamine, stearylamine, oleylamine, etc., basic amino acids such as lysine, histidine, ornithine, arginine, etc., sterols such as cholesterol, cholestanol, etc., phosphatidic acids and charged substances such as gangliosides and stearylamine. Those substances can be used not only singly or in a suitable combination of more than one species.
The amount of such supplemental components in the emulsion of the invention should vary with intended uses of the emulsion and other factors but the recommended amount is generally not greater than 2 w/v %, preferably not greater than 1 w/v %.
In addition, various additives such as antioxidant, preservative, isotonizing agent, buffer, stabilizer, etc., auxiliary substances and nutrients may also be optionally added. Specifically, benzoic acid, ascorbic acid, tocopherol, etc. can be mentioned by way of example. Those substances can be generally incorporated in suitable amounts and the level of addition below 10 w/v % is sufficient.
The average particle diameter of the fat emulsion particles of the invention is 5-50 nm, preferably 5-40 nm, more preferably 10-30 nm.
While the fat emulsion particles of the invention exist as dispersed in water, the water may for example be tap water, purified water, distilled water or water for injection.
The emulsion of the invention can be lyophilized to provide a freeze-dried preparation. However, since the emulsion of the invention, which is intended for medical use, should be such that when redissolved in water or dissolved in the digestive tract, the freeze-dried preparation may reconstitute itself into a substantially original emulsion, it is preferable to formulate an excipient for that purpose (a lyophilization auxiliary agent). The excipient mentioned above includes but is not limited to saccharides. Preferred are disaccharides, and as specific examples, maltose, trehalose, and sucrose can be mentioned. In particular, maltose is preferred.
The amount of said excipient in the emulsion of the invention should vary with different species of the; excipient and other components but may judiciously be selected from the range of 1-30 w/v %, more preferably 3-20 w/v %.
The emulsion of the invention can be produced by the conventional technology. An exemplary production process comprises adding the drug, said emulsifier, optionally as well as bile acid and/or a salt of bile acid and other additives in suitable amounts to a predetermined amount of the oil component, homogenizing the mixture with or without heating, adding a suitable amount of water, and emulsifying the whole mixture with a homogenizing machine such as the conventional homo-mixer, homogenizer, ultrasonic homogenizer, Microfluidizer (brand name), Nanomizer (brand name), Ultimizer (brand name) or Manton-Gaulin pressure homogenizer.
The freeze-dried version of the emulsion of the invention can be manufactured by lyophilizing the emulsion of the invention by the conventional technology. An exemplary process comprises sterilizing the emulsion of the invention, dispensing the emulsion in predetermined amounts into vials, performing preliminary lyophilization at about xe2x88x9240-xe2x88x9220xc2x0 C. for about 2 hours, then performing primary drying under reduced pressure at about 0-10xc2x0 C. and finally performing secondary drying under reduced pressure at about 15-25xc2x0 C. This sequence is generally followed by purging the internal air of the vials with nitrogen gas and stoppering the vials to provide the objective freeze-dried version of the emulsion of the invention.
The freeze-dried preparation of the invention can be directly administered without redissolving it in advance. Optionally, it can be first reconstituted by adding a suitable solution (a reconstitution medium) with or without the aid of stirring for redissolution and, then, administered. The reconstitution medium includes but is not limited to tap water, purified water, distilled water, water for injection, physiological saline, general infusions and drinking water. The proportion of the reconstitution medium is not particularly restricted but may judiciously be 0.5-2 times the volume of the emulsion prior to lyophilization or not greater than 500 ml.
The freeze-dried preparation according to the invention can be pulverized and, optionally after addition of a suitable excipient, be processed into fine granules, powders, capsules and liquids (inclusive of syrups) or compression-molded together with a suitable excipient to provide tablets. Those tablets can be coated with a suitable coating agent.
The emulsion of the invention or the freeze-dried version thereof can be administered, whether as it is or after redissolution and/or suitable processing, orally to animals inclusive of humans.
The following examples and test examples illustrate the invention in further detail.